Polymorphism

When a substance exists in more than one crystalline form, the different form are designated as polymorphs and the phenomenon as polymorphism.

1. POLYMORPHISM Mr. Sagar Kishor Savale Department of Pharmaceutics [email protected] 2015-016 4/19/2016 Sagar Kishor Savale 1 1

2. List of contents:- 4/19/2016 Sagar Kishor Savale 2 Definition Need to study polymorphism ( rational for selecting polymorph) Types of polymorphism How to differentiate them Pseudo polymorphism Properties Method for identify polymorphism Significance of polymorphism Conclusion References

3. Definition 1,2 When a substance exists in more than one crystalline form, the different form are designated as polymorphs and the phenomenon as polymorphism. e.g.:- carbon: diamond in a cubic ( tetrahedral lattice arrangement ) Graphite in sheet of a hexagonal lattice. 4/19/2016 Sagar Kishor Savale 3

4. True polymorphs can be classified into two different types 2 4/19/2016 Sagar Kishor Savale 4 Enantiotropic — on e polymorp h ca n b e reversibly change d int o anothe r on e b y varyin g th e temperature o r pressure. eg. sulfur Monotropic — th e chang e betwee n th e tw o form s is irreversible . eg. Glyceryl stearates

5. Difference between enantiotropy and monotropy. 3 Enantiotropic pair monotropic pair Reversible phase transition Irreversible phase transition Metastable stable Metastable stable Transition is endothermic Transition is exothermic Lower melting form is thermodynamically stable below the transition temp.. And higher m.p . form is stable above the transition temp.. Higher melting form is always thermodynamically stable form. lower m.p. has lower heat of fusion. Higher m.p. has high heat of fusion. 4/19/2016 Sagar Kishor Savale 5

6. Method to identify polymorphism. 3 Optical crystallography: Use in the identification of polymorphs crystal exist in isotropic and anisotropic form Isotropic examine the velocity of light is same in all direction Anisotropic crystal have 2 or3 different light velocities or refractive index. Video recording system and polarizing microscope fitted during according to heating and cooling stage for investigating polymorph. cont… 4/19/2016 Sagar Kishor Savale 6

7. Application To study of degree of stability of metastable form. Transition temperature Melting point Rate of transition under various thermal and physical condition. Whether to peruse polymorphism as a route to an improved dosage form. 4/19/2016 Sagar Kishor Savale 7

8. Hot stage microscope Fluid stage transformation as a function of temperature is observed Silicon oil stage microscopy is used for detection of pseudopolymorph. APPLICATION: in the study of solid-state active pharmaceutical ingredients (APIs), EXCIPIENTS and pharmaceutically relevant polymers and lipids. 4/19/2016 Sagar Kishor Savale 8

9. x ray diffraction method It provide the most complete information about solid state (identification & description) This method is based on the scattering of x-ray by crystals By this method one can identify the unit cell dimensions & conclusively establish the crystalline lattice system & provide specific differences between crystalline forms of given compound. In an X-ray diffraction measurement, a crystal is mounted on a goniometer and gradually rotated while being bombarded with X-rays, producing a diffraction pattern of regularly spaced spots known as reflections . It is tedious time consuming so it is not used or unsuitable for routine use. 4/19/2016 Sagar Kishor Savale 9

10. 4/19/2016 Sagar Kishor Savale 10 X ray diffraction pattern

11. Application many materials can form crystals—such as salts, metals, minerals, semiconductors, as well as various inorganic, organic and biological molecules—X-ray crystallography has been fundamental in the development of many scientific fields 4/19/2016 Sagar Kishor Savale 11

12. Melting point M.P. determination are often useful technique, but only when substance undergoing investigation heated through phase transition without decomposition. 4/19/2016 Sagar Kishor Savale 12

13. Differential Scanning Calorimetric (DSC ) DSC is also like to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition. When no physical or chemical changes is occurring within the sample then there is neither a temperature change nor the need to input energy to maintain an isotherm. Samples that may be studied by DSC or DTA are: Powders, fibers , single crystals, polymer films, semi-solids. DSC measures endothermic and exothermic transitions as a function of temperature. –Endothermic heat flows into a sample. –Exothermic heat flows out of the sample. 4/19/2016 Sagar Kishor Savale 13

14. 4/19/2016 Sagar Kishor Savale 14 Differential Scanning Calorimeter (TA Instruments Q10, Q 100,Q 1000)

15. Applications of DTA / DSC in preformulation studies 1. To determine the purity of a sample 2. To determine the number of polymorphs and to determine the ratio of each polymorph 3. To determine the heat of solvation . 4. To determine the thermal degradation of a drug or excipients . 5. To determine the glass-transition temperature(tg) of a polymer. 4/19/2016 Sagar Kishor Savale 15

16. Effect of polymorphism on bioavailability If the absorption of active ingredient in drug through G.I.T polymorphism is an important preformulation tool. Here successful utilization of polymorph having significant greater thermodynamic activity (solubility)may provide good therapeutic blood level from otherwise inactive drugs. Eg novobiocin . two different forms : crystalline and amorphous. In tablet or capsule formulation 4/19/2016 Sagar Kishor Savale 16

17. PSEUDO POLYMORPHISM 4 Term - pseudo means = false The phenomenon in which solvent molecules get incorporated into crystal lattice of solid are known as solvates . This solvates exist in different crystal form called pseuodopolymorph and the phenomenon is called as Pseudopolymorphism . also known as a hydrate when water is solvent. E.g.- synthetic estrogen ‘ethynylestradiol ’ is crystallized from the solvent acetonitrile , methanol , chloroform and saturated with water four different crystalline solvates are form. 4/19/2016 Sagar Kishor Savale 17

18. Differentiate pseudopolymorph form true polymorph. By observing melting behavior in silicon oil using hot stage microscopy. Here in this technique pseudopolymorph evolve the gas causing bubbling of the oil. While true polymorphs merely melts, forming second globular phase. 4/19/2016 Sagar Kishor Savale 18

19. Application For improvement of therapeutic activity of drug. To prevent loss of raw material. For better bioavailabity of drug. . 4/19/2016 Sagar Kishor Savale 19

20. Need to study polymorphism. 5 O ne of the several polymorphic form will be physically more stable than others . Stable polymorph represent s the lowest energy state, has highest melting point and least aqueous solubility. Metastable form represent the higher energy state , have lower melting point and high aqueous solubility . Metastable form converted to the stable form due to their higher energy state . Metastable form shows better bioavailability and therefore preferred in formulations. Cont.. 4/19/2016 Sagar Kishor Savale 20

21. Polymorphism is remarkably common particularly within certain structural group. E.g. – Cont.. 4/19/2016 Sagar Kishor Savale 21 CLASS %OF POLYMORPHISM Barbiturates 63 Steroids 57 Sulphonamides 40

22. Significance of studying polymorphism Different polymers exhibits different solubility, therapeutic & stability. The desire forms consistently manufactured. The effect of pharmaceutical manipulations are understood. E.g. granulation, milling & compression. Effect of storage condition on the dosage form can be evaluated & predicated. E.g. crystal growth in suspension, cream. 4/19/2016 Sagar Kishor Savale 22

23. Properties of polymorphs. 5 Polymorphs show the same properties in the liquid or gaseous state but they behave differently in solid state. Melting and sublimation temperature. Solubility and dissolution rate Stability Crystal habit Hygroscopicity Compression characteristics 4/19/2016 Sagar Kishor Savale 23

24. Conclusion Differences in the solubility and melting point must also be assessed and then a decision can be made to determine which form to progress through to the next stage. Metastable form may lead to a preferential choice of a polymorph other than stable form . As polymorphism can have such serious consequences for the bioavailability of drugs with low aqueous solubility . 4/19/2016 Sagar Kishor Savale 24

25. References M.E. Aultan, The science of dosage form design, 2 nd edition 2002, p.no 8,26,124-126,142-144. Brahmankar D. M., Sunil B. Jaiswal, Biopharmaceutics & Pharmacokinetics- A Treatise,1 st edition, Vallabh Prakashan, New Delhi 2007, p.no-27-29. Leon Lachman, Herbert A. Lieberman, The Theory Practice Of Industrial Pharmacy, 3 rd edition, Varghese Publication, Bombay 1987, p.no. 178-181, 230-231. Alfred Martin, James Swarbrick, Physical Pharmacy,3 rd , Varghese Publication, Bombay 1991, p.no. 72-73, 575-76. Encyclopedia of Pharmaceutical Technology 4/19/2016 Sagar Kishor Savale 25

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